Multiple myeloma (MM) is the second most common hematologic malignancy after non-Hodgkin's lymphoma, with an estimated 20,520 patients diagnosed with the disease and an estimated 10,610 deaths from MM in the U.S. in 2011.5,6 In 2016, there were an estimated 30,330 newly diagnosed cases in US, therefore accounting for ˜1.8% of all new cancer cases.7 The estimated prevalence of MM in U.S. is 65,000 patients.5 The incidence of MM increases with age, with the median age at diagnosis being 69 years.5 The most common signs and symptoms of MM include hypercalcemia, renal dysfunction, anemia, and bone lesions, the CRAB criteria8,9. Bone pain is often an initial symptom of the disease.10 Symptoms often require specific management in addition to direct anti-MM treatment strategies. FDA approved targeted agents, such as the proteasome inhibitor bortezomib (BOR), and thalidomide and lenalidomide, the immunomodulatory agents (IMiDs) have shown remarkable improvements in MM patients.11-13 While bortezomib (Velcade; Janssen-Cilag, Neuss, Germany) is a well-established therapeutic option in systemic light chain (AL) amyloidosis, the combination therapy involving cyclophosphamide, bortezomib, and dexamethasone (CyBorD) has shown promising effects in MM patients.14-16 Recent clinical studies in a cohort of 70 MM patients show higher concentration of κ and λ soluble free LC (sFLCs) than their counterparts without amyloidosis, while also indicating highest concentration of κ and λ sFLCs in the group of patients with amyloidosis and renal failure.17 These data indicate that sFLCs concentrations could be employed as critical biomarker for differentiation of MM patients with or without amyloidosis and provide guidelines for stratification of a pool of patients susceptible to a risk factor for renal failure.
Importantly, although both AL amyloidosis and MM are caused by clonal plasma cells, the two disorders present surprisingly different phenotypes. AL amyloidosis leads to deposits of amyloid protein aggregates in various organs (e.g., kidney, heart, liver, spleen, peripheral nerves, GI tract) resulting in impairment of their normal function. Within symptomatic MM patients, accumulation of clonal plasma cells and monoclonal immunoglobin proteins mediated by hypercalcemia, renal insufficiency, anemia and osteolytic bone lesions (CRAB criteria) results in the organ failure.18 While amyloid plaques are ascertained via histochemical staining of biopsied specimens using Congo red; MM patients have been shown to be amyloid positive yet Congo red negative. The lack of a clear biochemical distinction between MM and AL mandates discovery and development of ultrasensitive and specific agents for detecting AL amyloidosis in vitro and in vivo. Given that direct confirmation of AL amyloidosis through laser-driven micro-dissection and mass spectrometry analysis is confined to a few facilities nationwide, ultrasensitive diagnostic noninvasive agents capable of detecting AL amyloidosis are urgently mandated. These agents could allow stratification of MM patients for therapeutic interventions and monitor efficacy of therapeutics. This stratification continues to be the most desirable yet an unmet goal in the management of MM.